Fever, Neonate

Article Author:
Usha Avva
Article Editor:
Carlee Lenehan
10/27/2018 12:31:35 PM
PubMed Link:
Fever, Neonate


The neonatal sepsis is categorized into early and late based on the age of onset. Early neonatal sepsis affects infants less than 72 hours of age; whereas, late-onset infections are seen in infants older than 72 hours to 28 days of age. Early recognition and appropriate treatment are necessary to decrease the significant morbidity and mortality in this age group.


The etiology of early-onset neonatal sepsis is predominantly GBS infection followed by Escherichia coli sepsis. Risk factors are maternal Group B streptococcal colonization, chorioamnionitis, premature or prolonged (greater than 18 hours) rupture of membranes, preterm birth (less than 37 weeks) and multiple gestations.

The etiology of late-onset neonatal sepsis is from pathogens like Guillain-Barre syndrome (GBS), E. coli, Coagulase-negative Staphylococci, Staphylococcus aureus, Klebsiella pneumonia, Enterococci (more common in preterm infants), Pseudomonas, and Candida albicans. Risk factors for late-onset neonatal sepsis are prematurity, low birth weight, prolonged indwelling catheter use, invasive procedures, ventilator-associated pneumonia, and prolonged antibiotic usage.


WHO statistics say more than one million neonatal deaths around the world each year are caused by neonatal sepsis/pneumonia making it leading cause of infant mortality, whereas pre-term infants are more at risk for the neonatal sepsis in the United States. According to the Centers for Disease Control and Prevention (CDC), the incidence of early-onset neonatal sepsis in the United States is estimated to be 0.77 to 1 per 1000 live births. With the establishment of guidelines in universal screening and treating maternal GBS colonization, the incidence of early-onset sepsis in full-term infants has decreased to 0.3 to 0.4/1000 live births.


Recognition of pathogen by the local immunity is accomplished by the activation of the pattern recognition receptors (PRR) like extracellular, toll-like receptors (TLRs) and intracellular NOD-like receptors (NLR) and RIG-like receptors (RLR). Gram-positive, gram-negative sepsis activates TLR2 and TLR4 respectively; whereas, the double-stranded virus activates TLR3. They initiate an immune response by producing proinflammatory cytokines which in turn cause endothelial activation and damage causing SIRS, sepsis, and death. Premature neonates show dysregulation complement system making them susceptible to severe sepsis.


Host defense proteins like opsonin (CRP), haptoglobin, lactoferrin, serum amyloid A and procalcitonin provide additional protection.  Septic neonates have decreased the production of Interleukins (IL-1beta, TNF-alpha, IEN-gamma, and IL-12). The quantitative and qualitative deficits in neutrophils, neutrophil depletion of bone marrow and their decreased deformability and delayed apoptosis play a significant role in neonatal sepsis-causing endothelial damage, DIC, and multi-organ failure.

History and Physical

Neonatal sepsis has a varied presentation. The neonate could have hypo or hyperthermia, irritability or lethargy, apnea or tachypnea, bradycardia or tachycardia, poor feeding, excessive sleepiness or simply being fussy. Necrotizing enter colitis is common in premature and very premature infants. The physical examination could be noncontributory or could show an ill-looking infant with abnormal or unstable vital signs.

A careful history is very important. History should include both maternal and infant risk factors. Maternal risk factors are prenatal care, maternal colonization, intrapartum antibiotic use, maternal medical history including diabetes, hypertension, thyroid disease and maternal drug abuse. Infant risk factors are prematurity, birth weight, neonatal course, detailed history of NICU stay, length of ruptured membranes, ill contact and detailed feeding history.


Obtain white cell count, chemistry panel, and cultures of the blood, urine, cerebrospinal fluid (CSF), and body fluid. Microscopic analysis of urine, CRP, and procalcitonin are used in the risk stratification process to identify infants at low risk for serious bacterial infection. Respiratory Pathogen panel or tests for RSV, influenza, gastrointestinal (GI) pathogen panel, a chest x-ray could be obtained based on the symptoms. Rochester criteria, Philadelphia criteria, and Boston criteria all call for full septic work up in infants less than 28 days of age regardless of their risk factors. With the advent of the streptococcal vaccination, the prevalence of bacteremia in febrile infants has decreased. Gomez et al. validated “Step by Step” approach (Pediatrics, August 2016), which showed that the risk stratification is a workable strategy to identify low-risk infant with fever. Infants with fever at high risk for serious bacterial infection have elevated leukocyturia, elevated procalcitonin (greater than 0.5 ng/ml), CRP(greater than 20 mg/L) and ANC (greater than 10,000/mm3). Wallace and Brown et al. (Journal of Pediatrics, May 2017) showed that the frequency of bacterial meningitis with urinary tract infection (UTI) is minimal. Greenhow et al. concluded that 24% of the well-looking neonates with fever born at Kaiser Permanente Northern California did not have any laboratory studies done and none of them had delayed bacteremia or meningitis. Recently some centers are using the CSF molecular testing which has a turn around time of two hours to aid in the management of febrile neonates, especially during the enteroviral season. This test is also useful if the CSF is bloody are very abnormal to differentiate between bacterial and viral pathogens.

Treatment / Management

The ill-looking child requires full septic work and broadspectrum antibiotic coverage with ampicillin and cefotaxime, the combination of which covers 100% of early neonatal infections and 93% of late-onset bacteremia. Gentamycin and penicillin can cover 94% of early infections. Cefotaxime is not sufficient to treat some Escherichia coli, Pseudomonas, Enterococci, Acinetobacter, and Listeria monocytogenes. Use of Cefotaxime in the NICU can cause outbreaks of drug-resistant nosocomial infections, which is a serious concern in many centers. Empiric treatment of neonatal herpes with Intravenous Acyclovir is considered if the CSF has elevated red cell count or in any ill-looking neonate where herpes is suspected. Ill looking infants and infants with risk factors should be admitted and treated empirically while waiting for the cultures.

Fluid resuscitation is different to treat septic shock. In term neonate, the fluid bolus is 20 mL/kg as rapidly as possible up to 60 mL/kg, whereas in preterm neonate the fluid bolus consists of 10 mL/kg in 30 minutes and repeat if needed and then vasopressor support for the fluid refractory shock with dopamine and dobutamine. For catecholamine-resistant shock consider milrinone (cold shock with poor LV function and normal blood pressure, nitrous oxide (for low blood pressure and poor RV function), vasopressin, or terlipressin in conjunction with inotropes (for warm shock and low blood pressure)and consider ECMO.

Well looking febrile infants greater than 21 days of age without any risk factors and without any source of invasive infection can be risk stratified into high risk, medium risk and low risk based on the laboratory data. Low-risk infants can be safely observed at home or in the hospital without empiric treatment. High-risk infants should be treated and observed in the hospital. Medium-risk infants could be observed before treating them empirically. If in doubt admit them to the pediatric unit for observation while waiting for the culture results.

Differential Diagnosis

The differential that should be entertained are:

  • Hypoglycemia
  • Congenital heart disease
  • Inborn errors of metabolism.
  • Congenital adrenal insufficiency
  • Congenital hypothyroidism
  • Neglect/abuse


Prognosis is excellent if treated early in full-term neonates. The prognosis is different in premature and very premature infants.